One-Pot Cyclization to Large Peptidomimetic Macrocycles by In Situ-Generated β-Turn-Enforced Folding
Fei Gou, Di Shi, Bohan Kou, Li Zhao, Xiaosheng Yan, Xin Wu, Yun‐Bao Jiang
Abstract
Macrocycles have been targets of extensive synthetic efforts for decades because of their potent molecular recognition and self-assembly capabilities. Yet, efficient syntheses of macrocyclic molecules via irreversible covalent bonds remain challenging. Here, we report an efficient approach to large peptidomimetic macrocycles by using the in situ-generated β-turn structural motifs afforded in the amidothiourea moieties from the early steps of the reaction of 2 molecules of bilateral amino acid-based acylhydrazine with 2 molecules of diisothiocyanate. Four chiral and achiral peptidomimetic large macrocycles were successfully synthesized in high yields of 45–63% in a feasible one-pot reaction under sub-molar concentration conditions and were purified by simple filtration. X-ray crystallographic characterization of three macrocycles reveals an important feature that their four β-turn structures, each maintained by four 10-membered intramolecular hydrogen bonds, alternatively network the four aromatic arms. This affords an interesting conformation switching mode upon anion binding. Binding of SO 4 2– to 1L or 1D that contains 4 alanine residues (with the lowest steric hinderance among the macrocycles) leads to an inside-out structural change of the host macrocycle, as confirmed by the X-ray crystal structure of 1L -SO 4 2– and 1D -SO 4 2– complexes, accompanied by an inversion of the CD signals. On the basis of the strong sulfate affinity of the macrocycles, we succeeded in the removal of sulfate anions from water via a macrocycle-mediated liquid–liquid extraction method. Our synthetic protocol can be easily extended to other macrocycles of varying arms and/or chiral amino acid residues; thus, a variety of structurally and functionally diverse macrocycles are expected to be readily made.